title: Essential role for the Mnk pathway in the inhibitory effects of type I interferons on myeloproliferative neoplasm (MPN) precursors.
abstract: The mechanisms of generation of the antineoplastic effects of interferons (IFNs) in malignant hematopoietic cells remain to be precisely defined. We examined the activation of type I IFN-dependent signaling pathways in malignant cells transformed by Jak2V617F, a critical pathogenic mutation in myeloproliferative neoplasms (MPNs). Our studies demonstrate that during engagement of the type I IFN receptor (IFNAR), there is activation of Jak-Stat pathways and also engagement of Mnk kinases. Activation of Mnk kinases is regulated by the Mek/Erk pathway and is required for the generation of IFN-induced growth inhibitory responses, but Mnk kinase activation does not modulate IFN-regulated Jak-Stat signals. We demonstrate that for type I IFNs to exert suppressive effects in malignant hematopoietic progenitors from patients with polycythemia vera, induction of Mnk kinase activity is required, as evidenced by studies involving pharmacological inhibition of Mnk or siRNA-mediated Mnk knockdown. Altogether, these findings provide evidence for key and essential roles of the Mnk kinase pathway in the generation of the antineoplastic effects of type I IFNs in Jak2V617F-dependent MPNs.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Swarna
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Bhumika
authors.initials: B
authors.lastname: Sharma
authors.forename: Sonali
authors.initials: S
authors.lastname: Joshi
authors.forename: Barbara
authors.initials: B
authors.lastname: Kroczynska
authors.forename: Beata
authors.initials: B
authors.lastname: Majchrzak
authors.forename: Brady L
authors.initials: BL
authors.lastname: Stein
authors.forename: Brandon
authors.initials: B
authors.lastname: McMahon
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D016899:Interferon-beta; C491395:MKNK1 protein, human; D053612:Janus Kinases; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Antiviral Agents; Innate Immunity; Interferon; MAP Kinases (MAPKs); Phosphatidylinositol 3-Kinase; RNA; Translation Control; Translation Initiation Factors